Antibody production is very difficult when it is difficult to express and purify the target antigens necessary to produce the antibodies. This tendency is pronounced for membrane proteins. Therefore, a technique has been developed which uses proteins that are difficult to express or purify, such as seven-transmembrane proteins, as antigens by expressing the antigenic proteins on the membrane surface of the Autographa californica nuclear polyhedrosis virus (AcNPV), which belongs to Baculovirus (Non-Patent Document 1).
However, although baculovirus expression systems are useful as expression systems for various proteins comprising membrane proteins, there are many gp64 membrane proteins (Non-Patent Documents 2 and 3) on the surface of baculoviruses, and these contaminate the expression products obtained from baculovirus expression systems. gp64 is a 64-kDa protein, a major component of the surface of budding viruses, and known to be a protein involved in envelope fusion at low pH. This gp64 is more easily recognized as non-self than human-derived antigenic proteins, and when gp64 contaminates immunogens, antibodies are produced more readily against gp64 than against the target antigens. Therefore, when preparing immunogens using a baculovirus expression system, it is difficult to produce and obtain specific antibodies against antigenic proteins (Non-Patent Document 4). As a means to solve this problem, the present inventors generated gp64 transgenic mice (hereinafter referred to as “Tgm”). Before their immune system develops, these Tgm (hereinafter referred to as “gp64Tgm”) carry an exogenous gp64 in the same way as the endogenous genes. Therefore, these Tgm show immunotolerance against gp64, just as they do for the endogenous genes. Thus they recognize target antigenic proteins expressed using baculovirus, enabling the advantageous production of specific antibodies (Patent Document 1).
However, the gp64Tgm showed a phenotype with no testes development nor sperm formation. Therefore, the maintenance of the strain was restricted to females, and although the strain could be maintained, efficient breeding was not possible. In addition, there were some difficulties when producing crossbred animals by crossing with other knockout mice or Tgm.    [Patent Document 1] WO 03/104453.    [Non-Patent Document 1] Biotechnology, vol. 13, 1079-84, 1995.    [Non-Patent Document 2] Journal of Immunological Methods, vol. 234, 123-135, 2000.    [Non-Patent Document 3] Journal of Virology, vol. 70, No. 7, 4607-4616, 1996.    [Non-Patent Document 4] Journal of Virology, vol. 69, No. 4, 2583-2595, 1995.